The enrolment was prematurely terminated after the planned monitoring of the first 5 patients because of an unacceptable level of relevant toxicities, according to statistical stopping rules and the DSMB recommendation.

FIL_Dara-GDP is a phase II, open label, multicenter clinical trial. The sponsor of this clinical trial is Fondazione Italiana Linfomi (FIL). The primary objective is to evaluate the efficacy of 4 courses of D-GDP (Daratumumab in combination with Gemcitabine, Cisplatin, Dexamethasone) in terms of complete response in patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL) and other nodal lymphomas of T follicular helper cells (TFH cells) origin refractory/relapsed after at least one and no more than two previous lines of therapy.

This is an open-label, multicenter, single arm, single-stage phase II trial. After the patient signs the written informed consent the patient will enter the screening phase planning baseline assessments and a concomitant upfront confirmation of diagnosis of Peripheral T-Cell Lymphoma Not Otherwise Specified (PTCL-NOS), Angioimmunoblastic T-cell lymphoma (AITL) or Nodal Lymphoma of T Follicular Helper cells (TFH cells) origin and a central evaluation of immunohistochemical positivity of CD38 (cluster of differentiation 38) on bioptic material used to perform local diagnosis of relapsed disease, or that used for the more recent biopsy in the case of refractory patients. A core needle biopsy is considered sufficient for review and CD38 evaluation. Evaluation at central laboratory can be performed in bone marrow sections in those patients with only bone marrow lymphoma infiltration.

Only patients with confirmed eligible diagnosis and a percentage of CD38 positive tumor cells ≥ 5% will be considered eligible for study treatment.

The treatment consists of an induction phase and a maintenance phase.

Induction phase:

4-6 courses (according to response after cycle 4 and to patient compliance) of D-GDP (Daratumumab in combination with Gemcitabine, Cisplatin, Dexamethasone) every 21 days pursuant to the following schedule:

• Daratumumab cycle 1: 8 mg/kg i.v. on day 2 and on day 9; cycle 2-6: 16 mg/kg i.v. on day 2 and day 9)
• Gemcitabine 1000 mg/sm i.v. day 1 and day 8 (gemcitabine on day 8 to be skipped in case of grade 3-4 toxicity)
• Cisplatin 75 mg/sm i.v. day 1
• Dexamethasone 40 mg i.v. or po days 1-2-3-4-9
• Granulocyte-colony stimulating factor (G-CSF) from day 3 to 6, and from day 10 to 13 (to be prolonged if necessary) After 4 courses of D-GDP (Daratumumab in combination with Gemcitabine, Cisplatin, Dexamethasone), patients in Complete Remission/Partial Remission (CR/PR) and eligible for allogeneic stem cell transplantation (allo-SCT) will be addressed to allo-SCT consolidation.

Otherwise, patients in Complete Remission (CR) will enter the maintenance phase at this point of the study.

Patients in Partial Remission (PR) (not eligible for allogeneic stem cell transplantation) or in Stable Disease (SD) after D-GDP x 4 cycles can receive 2 additional courses of D-GDP before maintenance or can move directly to maintenance, according to center choice (based on patient condition, performance status and quality of response).

Patients who respond (Complete Remission/Partial Remission) after 6 courses of induction phase (end of induction, EOI) and eligible to allogeneic stem cell transplantation (allo-SCT) will be addressed to allo-SCT consolidation.

Patients who respond to the induction phase (Complete Remission/Partial Remission) and are not eligible for allogeneic stem cell transplantation (allo-SCT) and patients in stable disease (SD) at the End Of Induction (EOI), will move to the maintenance phase.

Patients in Progressive disease (PD) at any time will discontinue treatment, as well as patients experiencing at any time unacceptable toxicity.

Maintenance phase:

starting 28 days after the beginning of cycle 4 or 6 (or, in case of toxicity grade > 1, after toxicity is resolved) and up to 24 cycles from start of D-GDP (Daratumumab in combination with Gemcitabine, Cisplatin, Dexamethasone) according to the following schedule:

• Daratumumab 16 mg/kg single administration every 28 days

Treatment with D-GDP (Daratumumab in combination with Gemcitabine, Cisplatin, Dexamethasone) or daratumumab single agent will be discontinued before completion of 24 cycles in case of:

• decision of the investigator to consolidate D-GDP (Daratumumab in combination with Gemcitabine, Cisplatin, Dexamethasone) response with allogeneic stem cell transplant
• disease progression
• unacceptable toxicity
• withdrawal of consent
• investigator determines that further therapy is not in the patient's best interest (e.g., due to non-compliance, toxicity, etc.) Adverse events ("Common Terminology Criteria for Adverse Events", CTCAE v. 5.0) will be monitored from the first study-related procedure, throughout treatment, maintenance and for 30 days after the end of treatment with the study drug.

Safety monitoring and stopping rules:

In order to monitor the safety and the activity of the treatment in small cohorts of patients, the Bayesian approach of Thall et al. (1995), as extended by Thall and Sung (1998) will be used.

Monitoring of relevant toxicity after 4 cycles of D-GDP (Daratumumab in combination with Gemcitabine, Cisplatin, Dexamethasone) will be done to ensure that it is not higher than an acceptable toxicity of 30% (as defined in the safety endpoints) and the monitoring of activity after 4 cycles of D-GDP (Daratumumab in combination with Gemcitabine, Cisplatin, Dexamethasone) will be done to ensure that Complete Remission (CR) proportion is not lower than 40%.

The prior probability of toxicity and activity are modeled by beta distributions [Beta (0.6,1.4) and Beta (0.8,1.2), respectively].

The enrolment will be stopped if the posterior probability of the treatment being more toxic or less active than expected is greater than 95%.

The primary efficacy analysis will be performed after enrolment of 35 patients. The primary efficacy analysis will consist of an estimate of Complete Remission Rate (CRR) on the efficacy population after 4 cycles of D-GDP (Daratumumab in combination with Gemcitabine, Cisplatin, Dexamethasone) therapy, with 90% confidence intervals (according to 1-sided alpha error of 0.05). To conclude that the new treatment is promising, the minimum number of patients with a Complete Remission (CR) is 12/35.

The time-to-event functions (Overall Survival (OS) and Progression Free Survival (PFS)) will be estimated by the Kaplan-Meier product-limit method.

Subgroup analyses on primary efficacy parameter (Complete Remission Rate (CRR)) will be performed to assess the role of daratumumab maintenance and to explore potential prognostic role of CD38 expression. A logistic regression model will be used and the effect (Complete Remission Rate (CRR)) and its 95% Interval of Confidence (CI) will be presented.

For safety analysis, both at patient level and at therapy cycle level, summaries of incidence rates (frequencies and percentages) and intensity of individual adverse events by CTCAE (Common Terminology Criteria for Adverse Events (CTCAE)) v. 5.0 will be reported.

The results of this study will support the rationale of a phase III randomized trial if both efficacy and safety endpoints will be considered promising.

Inclusion Criteria:

• Histologically documented diagnosis of CD38 (cluster of differentiation 38) positive PTCL-NOS, AITL and other nodal lymphomas of TFH cell origin as defined in the 2017 edition of the World Health Organization (WHO) classification. Patients with only bone marrow involvement are eligible.

Note: Only patients with a centrally assessed percentage of CD38 positive tumor cells ≥ 5% in the relapse biopsy, or in the more recent biopsy in the case of refractory patients, will be considered eligible for protocol study treatment.

• Age 18-70 years

• Relapsed or refractory to one previous lines of treatment (autologous transplantation as a consolidation to the first line of therapy should not be considered a second line)

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) < 2

• At least one site of measurable nodal disease at baseline ≥ 2.0 cm in the longest transverse diameter as determined by CT scan (MRI is allowed only if CT scan cannot be performed). Note: Patients with only bone marrow involvement are eligible

• Adequate hematological counts defined as follows:

  • Absolute Neutrophil count (ANC) > 1.0 x 109/L unless due to bone marrow involvement by lymphoma
  • Platelet count > 100.000/mm3 unless due to bone marrow involvement by lymphoma

• Adequate renal function defined as follows:

  - Creatinine clearance ≥ 40 mL/min (Cockcroft-Gault formula)

• Adequate hepatic function per local laboratory reference range as follows:

  • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN)
  • Bilirubin ≤1.5 x upper limit of normal (ULN)(unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)

• Subject understands and voluntarily signs an informed consent form approved by an Independent Ethics Committee (IEC), prior to the initiation of any screening or study-specific procedures

• Subject must be able to adhere to the study visit schedule and other protocol requirements

• Life expectancy ≥ 3 months

• Women must be:

  • postmenopausal for at least 1 year (must not have had a natural menses for at least 12 months)
  • surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy),
  • completely abstinent (periodic abstinence from intercourse is not permitted) or if sexually active, be practicing two highly effective methods of birth control (e.g., prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double barrier method (e.g.: condoms, diaphragm, or cervical cap, with spermicidal foam, cream, or gel, male partner sterilization) as local regulations permit, before entry, and must agree to continue to use the same method of contraception throughout the study. They must also be prepared to continue birth control measures for at least 3 months after terminating treatment.
  • Women of childbearing potential must have a negative pregnancy test at screening

• Men must agree to use an acceptable method of contraception (for themselves or female partners as listed above) for the duration of the study. Men must agree to use a double barrier method of birth control and to not donate sperm during the study and for 3 months after receiving the last dose of study drug.

• Male even if surgically sterilized (i.e., status post vasectomy) must agree to 1 of the following:

  • practice effective barrier contraception during the entire study treatment period and through 3 months after the last dose of study drug, or
  • agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post ovulation methods for the female partner] and withdrawal are not acceptable methods of contraception)

Exclusion Criteria:

• Histological diagnosis different from CD38 positive PTCL-NOS, AITL, and other nodal lymphomas of TFH cell origin

• More than two lines of previous treatment (autologous stem cell transplant performed as part of consolidation to a previous line of therapy should not be considered as a line of therapy)

• Previous treatment with Gemcitabine or Platinum based regimens; patients who received a single course of Platinum based course (i.e. DHAP) are not excluded

• Prior therapy with monoclonal antibody anti CD38 (against cluster of differentiation 38)

• Concomitant experimental therapy

• Relapse after allo SCT

• Central nervous system (CNS) involvement with lymphoma

• Subject has received any anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, investigational therapy, including targeted small molecule agents within 14 days prior to the first dose of study drug

• Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) requiring treatment

• Subject is:

  • Known to be seropositive for human immunodeficiency virus (HIV)
  • Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-hepatitis B core antigen (HBc)] ± antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR
  • Known to be seropositive for hepatitis C (except in the setting of a Sustained Virologic Response(SVR), defined as aviremia at least 12 weeks after completion of antiviral therapy)

• Cardiovascular disease (NYHA class ≥2)

• Creatinine Clearance < 40 mL/min (Cockcroft-Gault formula)

• Significant history of neurologic, psychiatric, endocrinological, metabolic, immunologic, or hepatic disease that would preclude participation in the study or compromise ability to give informed consent

• Any history of other active malignancies within 3 years prior to study entry, with the exception of adequately treated in situ carcinoma of the cervix uterine, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin, previous malignancy confined and surgically resected with curative intent.

• Uncontrolled and/or active systemic infection (viral, bacterial or fungal)

• Evidence of any other clinically significant uncontrolled condition(s)

• If female, the patient is pregnant or breast-feeding

The endpoint was assessed after 26 months from the date of starting therapy in place of the planned 42 months, due the early interruption of the study

CTCAE

Due early termination, only 8 patients were enrolled in the study. The study highlight a high level of toxicity of the experimental treatment.